PROJECT SUMMARY/ABSTRACT Associations between heightened maternal psychological stress during pregnancy and increased risk of offspring psychopathology have been demonstrated repeatedly. Evidence points to the integral role of limbic- prefrontal brain systems (LPFS) in mental health outcomes, and the vulnerability of LPFS to early life stress. Methodological advances allow for examining LPFS in newborn infants, increasing capacity to isolate pre- from postnatal influences. The current proposal builds on this work in several key ways. First, although specific characteristics of psychological stress during pregnancy (e.g. intensity, variability, timing) appear to have important implications for offspring outcomes, research on this topic has yielded inconsistent findings. Second, the framework for understanding associations between maternal psychological stress during pregnancy and offspring brain systems remains correlational. This proposal seeks to increase specificity and advance causal understanding regarding the influence of maternal psychological stress during pregnancy on offspring LPFS. The applicant will examine a unique, existing longitudinal dataset of healthy mother-infant dyads (N=86) with extensive characterization of the prenatal environment and newborn structural and resting state functional connectivity MRI (sMRI and rs-fcMRI). Well suited analytic techniques will be used to identify characteristics of maternal psychological stress during pregnancy (based on 4-days of ecological momentary assessment [EMA] in each trimester) most strongly associated with newborn LPFS (K99, Aim 1). The applicant will then examine EMA measured psychological stress in relation to questionnaire-based stress measures and biological indicators (endocrine and immune/inflammatory) to identify less resource intensive alternative markers (K99, Aim 2). The R00 (Aim 3) will focus on a sample of pregnant women enriched for high levels of psychological stress. It will employ a randomized-controlled-trial of an established stress reduction intervention (Mindfulness- Based Cognitive Therapy=60, Cntrl=60) to test the hypothesis that intervention-induced reduction in maternal psychological stress will influence newborn LPFS. The applicant brings a unique background spanning the fields of DOHaD, developmental neuroscience and clinical science. During the K-phase she will extend her training in intervention research with a focus on intervention with pregnant women to test hypotheses stemming from DOHaD. Training in DOHaD will focus on learning analytic techniques for EMA data, and deepening understanding of maternal stress during pregnancy. Building on her strong foundation in developmental neuroscience, the applicant will gain advanced skills to ensure her success as an independent researcher. The team of mentors, Drs. Fair (developmental neuroscience), Buss (DOHAD), Caughey (clinical science and pregnancy) and McEvoy (preventive intervention during pregnancy), provide expertise in all core areas, span all levels of career stage, and bring an excellent record of obtaining independent funding and mentoring young scientists.